Validation of diacyl glycerolacyltransferase I as a novel target for the treatment of obesity and dyslipidemia using a potent and selective small molecule inhibitor

  • J Med Chem. 2008 Feb 14;51(3):380-3. doi: 10.1021/jm7013887.
Gang Zhao  1 ,  Andrew J Souers ,  Martin Voorbach ,  H Doug Falls ,  Brian Droz ,  Sevan Brodjian ,  Yau Yi Lau ,  Rajesh R Iyengar ,  Ju Gao ,  Andrew S Judd ,  Seble H Wagaw ,  Matthew M Ravn ,  Kenneth M Engstrom ,  John K Lynch ,  Mathew M Mulhern ,  Jennifer Freeman ,  Brian D Dayton ,  Xiaojun Wang ,  Nelson Grihalde ,  Dennis Fry ,  David W A Beno ,  Kennan C Marsh ,  Zhi Su ,  Gilbert J Diaz ,  Christine A Collins ,  Hing Sham ,  Regina M Reilly ,  Michael E Brune ,  Philip R Kym
Affiliations
  • 1. Metabolic Disease Research, Abbott Laboratories, Abbott Park, IL 60064, USA.
PMID: 18183944 DOI: 10.1021/jm7013887
Abstract

A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice.